Development of broad-spectrum halomethyl ketone inhibitors against coronavirus main protease 3CLpro

Usman Bacha, Jennifer Barrila, Sandra B. Gabelli, Yoshiaki Kiso, L. Mario Amzel, Ernesto Freire

Research output: Contribution to journalArticle

Abstract

Coronaviruses comprise a large group of RNA viruses with diverse host specificity. The emergence of highly pathogenic strains like the SARS coronavirus (SARS-CoV), and the discovery of two new coronaviruses, NL-63 and HKU1, corroborates the high rate of mutation and recombination that have enabled them to cross species barriers and infect novel hosts. For that reason, the development of broad-spectrum antivirals that are effective against several members of this family is highly desirable. This goal can be accomplished by designing inhibitors against a target, such as the main protease 3CL pro (Mpro), which is highly conserved among all coronaviruses. Here 3CLpro derived from the SARS-CoV was used as the primary target to identify a new class of inhibitors containing a halomethyl ketone warhead. The compounds are highly potent against SARS 3CLpro with Ki's as low as 300 nm. The crystal structure of the complex of one of the compounds with 3CLpro indicates that this inhibitor forms a thioether linkage between the halomethyl carbon of the warhead and the catalytic Cys 145. Furthermore, Structure Activity Relationship (SAR) studies of these compounds have led to the identification of a pharmacophore that accurately defines the essential molecular features required for the high affinity.

Original languageEnglish (US)
Pages (from-to)34-49
Number of pages16
JournalChemical Biology and Drug Design
Volume72
Issue number1
DOIs
StatePublished - Jul 1 2008

Keywords

  • Biophysical chemistry
  • Calorimetric techniques
  • Drug design
  • Drug discovery
  • Protease and ligands (substrate/inhibitor)

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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